5-(gamma-amino-propyl- and propylidene-) 5h-dibenzo[a, d]-10-hydroxy-10, 11-dihydrocycloheptenes and amine borane salts thereof



United States Patent -(7-AMIN0-PR0PYL- AND PROPYLIDENE) SH-DI-BENZO[a,d]--HYDROXY 10,11 DIHYDROfiY- CLOHEPTENES AND AMiNE BORANE SALTSTHEREOF Janos Kollorjtsch, Westfield, Roger J. Tull, Piainfield, andAvery Rosegay, Springfield, N.J., assignors to gierck & (30., 1nd,Railway, N..l., a corporation of New ersey No Drawing. Filed Sept. 14,1962, Ser. No. 223,841) 21 Claims. (Cl. 266570.8)

This invention relates to 5H-dibenzo-[a,d]-10,1l-dihydrocyclohepteneswhich are substituted at the 5carbon atom with an aminopropyl oraminopropylidene radical and, more particularly, to such compoundshaving a 10- or ll-hydroxy substituent. The invention also includes anovel process for producing these compounds.

The compounds of the invention are useful in the treatment of mentaldisease in that they are anti-depressants and serve as mood elevators orpsychic energizers, and as intermediates for the preparation ofsecondary amines, some of which are members of a class havingpharmacological activity. For therapeutic purposes, they may beadministered in any of the usual pharmaceutical forms such as powders,capsules, tablets, elixirs, solutions and aqueous suspensions. The dailydosage is Within the range of from about 5 mg. to about 250 mg,preferably taken in divided amounts over the day, The compounds arepreferably administered in the form of their acid addition salts andthese salts are included within the scope of this invention.

The compounds formed herein may be represented by the general formula:

O I 10 l 11 1 X I X /1 H CH2CHZGH2NRR and 0H 10 I 11 I CHCHiCHzNRR whereR and R are similar or dissimilar and may be hydrogen, an alkyl radicalhaving up to 6 carbons, either straight or branched chain, or cycloalkylhaving up to 8 carbons or phenyl including phenyl substituted withhalogens, alkyl or alkoxy groups or aralkyl such as benzyl, providedthat when R and R are other than alkyl radicals the total number ofcarbon atoms in R and R does not exceed nine; where R and R are loweralkyl radicals, they may be linked together through an atom selectedfrom the group consisting of carbon, nitrogen and oxygen to form aheterocyclic ring having from five to six atoms therein such asl-piperidyl, l-pyrrolidyl, 4-morpholinyl and l-loweralkyl-4-piperazinyl; X and X are similar or dissimilar and are selectedfrom the group consisting of hydrogen, an alkyl group having up to 6carbon atoms, a perfluoroalkyl group having up to 4 carbon atoms, aphenyl or a substituted phenyl radical, amino, an alkylamino grouphaving up to 4 carbon atoms, a dialkylamino group having up to 8 carbonatoms, an acylamino group having up to 4 carbon atoms, a perilu- "iceoroacylamino group having up to 4 carbon atoms, an alkylsultonyl-aminogroup having up to 4 carbon atoms, halogen (fluorine, chlorine, bromineor iodine), hydroxyl, an alkoxyl group having up to 4 carbon atoms, aperfiuoroalkoxyl group having up to 4 carbon atoms, cyano, carbamyl, analkylcarbamyl group having up to 5 carbon atoms, a dialkylcarbamyl grouphaving up to 9 carbon atoms, a carbalkoxy group having up to 6 carbonatoms, mercapto, an alkylmercapto group having up to 4 carbon atoms, aperfluoroalkylmercapto group having up to 4 carbon atoms, analkylsulfonyl group having up to 4 carbon atoms, aperfluoroalkylsulfonyl group having up to 4 carbon atoms, sultamyl, analkylsulfarnyl group having up to 4 carbon atoms, or a dialkylsulfamy-lgroup having up to 8 carbon atoms; more than one of these substituentsmay be on each benzenoid ring. The compounds may have substituents onthe propyl and propylidene chains, such as lower alkyl radicals,preferably having from 1 to 4 carbon atoms.

Accordingly, typical compounds formed in accordance with the presentinvention are: 5-('ydimethylaminopropylidene)-5Hdibenzo-[a,d]-IO-hydroxycycloheptene; 5- (v-methylaminopropylidene) 5Hdibenzo-[a,d]-10-hydroxycycloheptene; 5-( y-dimethylaminopropyl)SH-dibenzo-[a,d]-10-hydroxycycloheptene; S-(y-methylaminopropyl-5H-dibenzo- [a,d] -1 O-hydroxycycloheptene; 5- aminopropylidene)5H-dibenzo-[a,d] IO-hydroxycycloheptene; and 5-(-aminopropyl)-5H-dibenzo-[a,d]-l0-hydroxycycloheptene.

The method of the present invention by which these compounds may beformed is illustrated schematically by the following flow sheet in whichthe dotted line at the S-carbon atom of the ring indicates that thecompounds may be saturated or unsaturated at this location, thesaturated compound being identified by a propyl and the unsaturatedcompound being identified as a propylidene chain, and X, X, R and R havebeen defined previously.

OHGHaCHzNRR'.

BRiRz oxidative hydrolysis /B In AKJHOII2CH2NRR' amine borane oxidationwhere R and R are selected from the group consisting of hydrogen, alkyland the organic radical:

CHCHzCHzNRR The process of the present invention begins with the knownaminopropyl or aminopropylidene compounds which are unsaturated at the10 and 11 positions. The preparation of these compounds is described innumerous places in the literature, for example, in British Patents Nos.858,187 and 858,188 and Belgian Patents Nos. 577,057 and 578,122. Thesecompounds are generally prepared from the known5I-I-dibenzo-[a,d]-cycloheptene- 5-ones which may be substituted with Xand X substituents. The starting compounds for the ketones, andparticularly those having substituents on the benzene rings, may be madeby following the teachings of T. W. Campbell et al. in an articleappearing in Helv. Chem. Acta, vol. 36, pp. 1489-1499 (1953).

Turning our attention now to the details of the process steps of thepresent invention, it is seen that the first step involves a novelhydroboration of an aminopropyl or aminopropylidene derivative of a5H-dibenzo-[a,d]- cycloheptene which is unsaturated at the and 11positions to form a 10 or 11 boron-substituted intermediate. In atypical run, 5-('y-methylaminopropyl)-5I-I-dibenzocycloheptene ishydroborated using diborane as the hydroborating agent to form the amineborane salt of a 10 or 1l-BH derivative of the starting compound.Suitable hydroborating agents are the borane aluminum alcoholates, suchas borane aluminum isopropylate, which reagent and its hydrocarbonequivalents are described in United States Patent 2,903,470. Other boroncompounds suitable for use in this reaction contain at least one BH bondin the molecule as, for example, in such compounds as diborane,amineboranes, alkyl boranes, aryl boranes, alkyl-aryl boranes andsuitably the aforementioned borane aluminum alcoholates.

When a reactive hydroborating agent, such as diborane, is used in thehydroborating step, the reaction is preferably carried out in an inertsolvent, such as tetrahydrofuran. On the other hand when a less reactiveagent is used, such as borane aluminum alcoholate, the hydroboration maybe carried out in the absence of a solvent. Preferably the reaction isconducted under a protective nitrogen atmosphere in order to preventoxidation of any of the boron compounds.

Where the starting compound contains a propylidene side chain, it isdesirable to carry out the reaction under conditions which disfavoraddition across the exocyclic double bond of the propylidene group.Preferably, a minimum reaction temperature and time are used at whichonly the endocyclic or 10,11-unsaturated bond will react. Also, not morethan two moles of hydroborating agent are used..

Once the double bond at the 10 and 11 positions of the aminopropyl oraminopropylidene compound has been opened by the addition of the boranecompound thereto, the desired hydroxy group may be formed at thislocation by oxidatively hydrolyzing the borane group to a hydroxy group.Suitably, the hydrolysis is carried out in a basic aqueous alcoholicsolution containing the oxidizing agent. A typical oxidative hydrolysismedium is an aqueous solution of sodium hydroxide in methanol containinghydrogen peroxide, although others may be used as well. In a typicalrun, the amine borane salt of a 10 or 11-BH substituted derivative of5-( -methylaminopropyl)-5H-dibenzo-[a,d]-cycloheptene is subjected tooxidative hydrolysis to form the amine borane salt of a 10 or ll-hydroxyderivative of S-(y-methylaminopropyD- dibenzo-[a,d]-cycloheptene.

The final step in the preparation of the novel compounds of the presentinvention involves an oxidation of the amine borane salt to the freeamine. This oxidation is preferably carried out using oxidizing agentscapable of converting the amine boranes to free amines. A preferredoxidizing agent for efiecting this step is iodate ion, although otheroxidizing agents may be used as well. Finally, purification andseparation of the desired product from the reaction mixture affords thedesired hydroxy compound in high yield.

It will be appreciated by those skilled in the art that the compounds ofthe present invention are capable of existing in one or more isomericforms. These forms may be isolated from the reaction mixture byseparation procedures known in the art as, for example, by thechromatographic technique described in detail in the examples.

The following more detailed examples will serve to further illustratethe present invention.

EXAMPLE I 5- (y-methylaminopropyl) -5H-dibenzo- [a,d] -10-hydroxy-10,11-dihydr0cycl0heptene A solution of 12.5 grams of5-('y-methylaminopropyl)- 5H-dibenzo-[a,d]-cycloheptene in 30 ml. ofdiethyl ether is added slowly to a solution of diborane in 75 ml. of a0.95 molar solution of tetrahydrofuran under a nitrogen atmosphere at 0C. After warming to room temperature and standing overnight, ml. ofmethanol is added slowly, followed by the addition of 85 ml. of 3 Nsodium hydroxide solution. Thereafter, 10 ml. of 30% hydrogen peroxidesolution is added at 25 C. and the mixture is stirred for 15 minutes atroom temperature, then for a few minutes at C. At this point ananalytical sample of the reaction mixture shows a positive peroxidetest. Thereafter, the organic solvents are removed by distillation invacuo at room temperature and the product is extracted with ether,washed with water, then with a mixture of dilute HCl and Na S Osolution, again with water, dried under MgSO and evaporated to drynessin vacuo to provide 14 g. of the amine borane salt of a5-('y-methylaminopropyl)-5H-dibenzo-[a,d]-l0-hydroxy- 10, ll-dihydrocycloheptene.

The amine borane salt thus obtained is dissolved in 200 ml. of methanoland oxidized by slow addition of 90 ml. of a 10% K10 solution at roomtemperature in 10 ml. of concentrated HCl. The run is complete when apresistent brown coloration due to the presence of iodine, is observed.The iodine then is removed by the addition of a small amount of sodiumthiosulfate. Thereafter, the pH is adjusted to about 8.5 by the additionof concentrated NaOH solution and subsequently all of the methanol isremoved by vacuum distillation. To the residue is added a water-in-ethermixture, the ether layer washed with water and the product extractedfrom the ether with 1 N HCl solution. The acidic extract extract then isalkalized and the base extracted with water, washed with saturated NaClsolution, dried over MgSO and evaporated to dryness in vacuo. 12.6 g. ofthe product is obtained from the residue, which is purified bycrystallization from an ethanol-isopropanol solution as the hemioxalate.After two recrystallations, the following analysis of the hemioxalate isobtained.

Caled. for C H ON (371.42): C, 67.9%; H, 6.78; N, 3.77%. Found: C,68.07%; H, 6.45%; N, 4.04%. M.P. 37 (under decomposition).

EXAMPLE II 5-(y-methylaminopropylidene) -5H-dibenz0- [a,d] -10-hydroxy-10,11-dihydr0cycl0heptene A solution of 52.2 grams (0.2 mole) of5-('y-methylaminopropylidene)-5H dibenzo [a,d] cycloheptene in 200 ml.of tetrahydrofuran is added slowly to a solution of diborane in 230 ml.of a 0.99 molar solution of tetrahydrofuran over nitrogen at 0 C. Afterwarming to room temperature and standing overnight, 150 mi. of methanolis added slowly, followed by the addition of 50 ml. of 5 N sodiumhydroxide solution. After stirring at 3-6, 38 ml. of 30% hydrogenperoxide solution is added during 30 minutes at 25 C. and the mixture isstirred for 90 minutes at room temperature followed by severaladditional minutes at 55 C. Then 200 ml. of water is added and theorganic solvents are removed by distillation in vacuo at roomtemperature. The resultant product is extracted with benzene, Washedwith water, then with a mixture of dilute HCl and Na SO solution, againwith water, dried under MgSO and evaporated in vacuo to dryness. Theproduct is the amine borane salt of a 5 methylaminopropylidene) 5Hdibenzo [a,d]- 1 -hydroxy-1 0,1 l-dihydrocycloheptene.

The amine borane salt then is dissolved in a mixture of 1000 ml. ofmethanol, 100 ml. of HCl and oxidized by slow addition of a 10% K10solution at 15 until an iodine coloration persists, which isdiscolorized by the addition of a small amount of sodium thiosulfate.Thereafter, the pH is adjusted to about 8.5 by the addition ofconcentrated NaOH solution and subsequently ail of the methanol isremoved by vacuum distillation. To the residue is added a water-in-ethermixture, the ether layer washed with water and the product extractedfrom the ether with 1 N HCl solution. The acidic extract then isalkalized and the base extracted with water, Washed with saturated NaClsolution, dried over MgSO and evaporated to dryness in vacuo. 12.6 g. ofthe prodnot is obtained from the residue. The product is purified bytransformation into the oxalic acid salt by the addition of 500 ml. of0.5 molar oxalic acid in isopropanol solution to 400 ml. of anisopropanol solution of the impure material. After two recrystallationsthe following analysis of the oxalate is obtained.

Calcd. for C H ON (369): C, 68.28%; H, 6.28%; N, 3.79%; Found: C,68.47%; H, 6.58%, N, 3.59%; U.V. spectrum in methanol: x 238 m E% 344.

EXAMPLE III 5 (y-dimethylamizzopropyl -5H -dibenz0- [a,d -1 0-hydroxy-l0,1I-dihydrocycloheptene Following the procedure described inExample I and using equivalent quantities of 5-('y-dimethylaminopropyl)-5H-dibenzo-[a,d]-cyc1oheptene in place of S-(-methylaminopropyl)-5H-dibenzo [a,d] cycloheptene there is produced thecorresponding hydroxy compound.

EXAMPLE IV 5 'y-dimethylaminopropy l i dene) -5 H -dibenz0- [a,d-hydr0xy-10,1J-dihydrocyclvheptene A mixture of 11.3 grams (0.041 mole)of S-(y-dimethylaminopropylidene)-5H-dibenzo [a,d] cycloheptene and 28.4grams (0.041 mole) of boranealuminum isopropylate (All-I (BI-I3Al(O-isopropyl) is heated for 2 /2 hours at 120-130 under nitrogenwhile stirring vigorously. At the beginning of the run a crystallizationoccurs while the borane salt of the starting amine compound separates;later the salt melts to a clear homogeneous mass. Then 50 ml. of benzeneis added and the excess of the borane compound is decomposed by thedropwise addition of 100 ml. of methanol under ice cooling. Thereupon,an oil is formed which is dissolved by the addition of ml. of 3 N NaOHfollowed by 10 ml. of H 0 during 15 minutes. After a KI paper reactionis observed to be negative, an additional 5 ml. of H 0 is added and themixture is stirred at room temperature for 2 hours. The mixture then isacidified with 3 N HCl, extracted with ether, the extracts washed withdilute HCl and water, dried over MgSO and evaporated to dryness. 11.0 g.of the amine borane salt of the desired hydroxy compound is obtained.

Thereupon, 5.0 grams of this intermediate is dissolved in 150 ml. ofmethanol and 10 ml. of concentrated HCl is added. The mixture then isoxidized by the dropwise addition of 20 ml. of 10% K10 solution withgentle warming at the end of the addition. The mixture is thenalkalized, the methanol evaporated to dryness in vacuo, the residuedistributed between water and ether, the ether layer washed with Water,extracted with 3 N HCl and the extract alkalized, extracted with ether,dried over MgSO, and evaporated to dryness to yield 3.7 grams of thedesired product. Chromatography on alumina using 1:1 benzene chloroformmixture as the eluent gives 1.7 grams of a solid from the benzene: 30%chloroform fraction. The crude product then is dissolved in Skelly Bsolvent from which 1.2 grams of colorless crystals result. Uponrecrystallization from methanol in Water there is obtained 0.41 gram ofa purified form of product. M.P. -132", U.V. in methanol 1 Inflection.

Analysis.C I-I ON: C, 81.9; H, 7.92; N, 4.78. Found: C, 81.64; H, 8.11;N, 4.82.

EXAMPLE V 5 -aminopropyl) -5 H -dibenz0? [a,d -1 O-hydroxy- 10,1 1-dihydrocycll0he p tene Following the procedure described in detail inExample I and using equivalent quantities of 5-('y-arninopropyl)5H-dibenzo-[a,d]-cycloheptene there is produced the correspondinghydroxy compound.

EXAMPLE VI 5- (y-aminopropylidene -5 H -dibenz0- [11,d 1 O-hydroxy- 10,1 l -dihydr0cycl0heptene Following the procedure described in detailin Example 11 and using equivalent quantities of 5-('-aminopropylidene)-5H-dibenzo-[a,d]-cycloheptene there is produced thecorresponding hydroxy compound.

EXAMPLE VII EXAMPLE VIII Separation and isolation of isomeric forms of5-(7- dimethylaminopropyliaene) SH-dibenzo-[adklO-hydroxy-Z 0,1 1-dihydr0cycl0heptene 40 grams of the purified form of5-(ql-dimethylaminopropylidene) 5H dibenzo[a,d]-10-hydroxy-10,1l-dihydrocycloheptene (Example IV) is dissolved inml. of benzene and chromatographed on 700 g. of alumina. Thechromatogram is developed by benzene, then with benzene-chloroformmixtures containing 10%, 25%, and 30% chloroform. In the 30%chloroform-containing mixture, 11.0 g. of a crystalline product isobtained. This is purified by triturating with hexane, followed byrepeated recrystallizations from benzene. Further purification isachieved by a second chromatography on alumina, followed byrecrystallizations from benzene. Large crystals are obtained, M.P. l356.

Paper chromatography indicates that the crystals are homogeneous.Nuclear magnetic proton resonance shows that this isomer contains ahydrogen bond, indicating that the OH group and the nitrogen atom areclose together in the molecule.

Further fractions of the chromatograms furnish the lower melting isomerwhich is purified by recrystallization from a hexane-benzene mixture togive crystals melting at 96". This isomer is observed to be nonhydrogenbonded, which suggests that the OH group and the nitrogen atom arefurther apart in space in the molecule.

Both isomers display considerable activity in animal tests for psychicenergizing activity.

What is claimed is:

1. A compound selected from the group having the formulae CHCHZCHZN andH OH2OH2CH2N\ and the non-toxic salts thereof, wherein R and R areselected from the group consisting of hydrogen and alkyl radicals havingup to 6 carbon atoms.

2. (y methylaminopropyl)-5H-dibenzo-[a,d]-10- hydroxy10,1l-dihydrocycloheptene.

3. 5 (y methylaminopropylidene)-5H-dibenzo-[a,d]- 10-hyrodxy-10,ll-dihydrocycloheptene.

4. 5 ('y dimethylaminopropyl)-5H-dibenzo-[a,d]-10- hydroxy-10,11-dihydrocycloheptene.

5. 5 ('y dimethylam-inopropylidene) 5H dibenzo-[a,d]-10-hydroXy-10,ll-dihydrocycloheptene.

6. 5 ('y aminopropyl)-5H-dibenzo-[a,d]-lO-hydroxy- 10,1l-dihydrocycloheptene.

7. 5 ('y iaminop'ropyl'id-ene) 5H dibenzo-[a,d1-l0-hydroxy-10,1l-dihydrocycloheptene.

8. The isomer of 5-('y-dimethylaminopropylidene)-5H- dibenzo [a,d]10-hydroxy-10,1l-dihydrocycloheptene having a melting point of 135-36C., said isomer having a hydrogen bond between the hydroxyl group andthe nitrogen atom of the amine group.

9. The isomer of 5-(y-dimethylaminopropylidene)-5I-I- dibenzo [a,d]l0-hydroxy-10,ll-dihydrocycloheptene having a melting point of 96 C.,said isomer lacking a hydrogen bond between the hydroxyl group and thenitrogen atom of the amine group.

10. A compound selected from the group having the formulae RI wherein Rand R are selected from the group consisting d of hydrogen and alkylradicals having up to 6 carbon atoms.

11. The amine borane salt of S-(y-methylaminopropylidene) 5H dibenzo[a,d]-l0-hydroxy-l0,1l-dihydrocycloheptene.

12. The amine borane salt of S-( y-methylarninopropyl) 5Hdibenzo-[a,d]-10-hydroXy-10,ll-dihydrocycloheptene.

13. The amine borane salt of S-(y-dimethylaminopropylidene) 5Hdibenzo-[a,d]-10-hydroxy-10,1l-dihydrocycloheptene.

14. The amine borane salt of 5-( -dimethylaminopropyl) 5Hdibenzo-[a,d]-l0-hydroxy-10,ll-dihydrocycloheptene.

15. A method of making compounds of the formulae CHCH CHZNRR' wherein Rand R are selected from the group consisting of hydrogen and alkylradicals having up to 6 carbon atoms, which comprises oxidizing theamine borane salt of the formulae IBHs CHOHZCHZNRR 13H; H OHQCHQGHZNRRwherein R and R are as defined, to produce the desired compound.

16. A method of making 5-('y-methylaminopropyl)- 5H dibenzo[a,d]10-hydroXy-1O,1l-dihydrocycloheptene which comprises hydroboratingS-(v-methyIaminopropy1)-5H-dibenzo-[a,d]-cyoloheptene with diborane inan inert solvent, oxidatively hydrolyzing the hydroborated productthereof to form the amine borane salt of 5-('ymethylaminopropyl) 5Hdibenzo [a,d]-IO-hydroxy- 10,1l-dihydrocycloheptene and oxidizing theamine borane group of the salt with iodate ion to form the desiredcompound.

17. A method of making 5-('y-dimethylaminopropylidene) 5H dibenzo[a,d]-10-hydroxy-10,1l-dihydrocycloheptene which comprises hydroborating5 dimethylaminopropylidene) 5H dibenzo-[a,d1-cycloheptene with boranealuminum isopropylate, oxidatively hydrolyzing the product of thehydroboration to form the amine borane salt of the desired product andoxidizing the amine borane group of the salt with iodate ion to form thedesired compound.

18. A method of making 5-('y-methylarninopropyl)- 5H dibenzo [a,d]10-hydroxy-10,1l-dihydrocycloheptene which comprises hydroborating 5-(-methylaminopropyl) 5H dibenzo [a,d]-cycloheptene with diborane in aninert solvent at about C., oxidatively hydrolyzing the hydrohoratedproduct thereof in basic solution with hydrogen peroxide to form theamine horane salt of -('y methylaminopropyl) 5H dihenzo[a,d]-10-hydroxy- 10,11-dihydrocycloheptene and oxidizing the amineborane group of the salt with iodate ion to form the desired compound.

19. A method of making 5-(' -dimethylaminopropylidene) 5H dibenzo[a,d]-10-hydroxy-l0,ll-dihydrocycloheptene which comprises hydroboratingS-(y-dimethylaminopropylidene) 5H dibenzo [a,d]-cycloheptene with boranealuminum isopropylate at about 130 C., oxidatively hydrolyzing theproduct of the hydroboration in basic solution with hydrogen peroxide toform the amine borane salt of the desired product and oxidizing theamine borane group of the salt with iodate ion to form the desiredcompound.

29. A method of making compounds of the formulae CHCHgCHaNRR or iwherein R and R are selected from the group consisting of hydrogen andalkyl radicals having up to 6 carbon atoms, which compriseshydroborating the corresponding 10,11-unsaturated compound andoxidatively hydrolyzing the product thereof to produce the amine boranesalt of the formulae I EH3 CHCHgCHgNRR' and oxidizing the amine boranegroup to produce the desired compound.

21. A method of making compounds of the formulae f? QE inomonmnrvReferences Cited by the Examiner UNITED STATES PATENTS 2,951,082 8/1960Sprague et a1. 3,073,847 1/1963 Doehel et a1. 260-570.5 XR

FOREIGN PATENTS 355,458 8/1961 Switzerland. 356,759 10/1961 Switzerland.356,760 10/ 1961 Switzerland.

OTHER REFERENCES Villani et al.: J our. of Medicinal and Pharm. Chem,vol. 5, No. 2, pages 373-83 (1962).

CHARLES B. PARKER, Primary Examiner.

1. A COMPOUND SELECTED FROM THE GROUP HAVING THE FORMULAE
 10. A COMPOUNDSELECTED FROM THE GROUP HAVING THE FORMULAE